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[Cancer Research 64, 7533-7544, October 15, 2004]
© 2004 American Association for Cancer Research

Regular Articles

Gonadotropin-Releasing Hormone (GnRH) Antagonists Promote Proapoptotic Signaling in Peripheral Reproductive Tumor Cells by Activating a G{alpha}i-Coupling State of the Type I GnRH Receptor

Stuart Maudsley1,2, Lindsay Davidson1, Adam J. Pawson1, Raymond Chan1, Rakel López de Maturana3 and Robert P. Millar1,4

1 Medical Research Council Human Reproductive Sciences Unit, Edinburgh, United Kingdom; 2 National Institutes of Health National Institute on Aging, Johns Hopkins Medical Center, Gerontology Research Center, Baltimore, Maryland; 3 Ardana Bioscience, Edinburgh, United Kingdom; and 4 Division of Medical Biochemistry, University of Cape Town Faculty of Health Sciences, Cape Town, South Africa

Gonadotropin-releasing hormone (GnRH) receptor agonists are extensively used in the treatment of sex hormone-dependent cancers via the desensitization of pituitary gonadotropes and consequent decrease in steroid sex hormone secretion. However, evidence now points to a direct inhibitory effect of GnRH analogs on cancer cells. These effects appear to be mediated via the G{alpha}i-type G protein, in contrast to the predominant G{alpha}q coupling in gonadotropes. Unlike G{alpha}q coupling, G{alpha}i coupling of the GnRH receptor can be activated by both agonists and antagonists. This unusual pharmacology suggested that the receptor involved in the cancer cells may not be the classical gonadotrope type I GnRH receptor. However, we have previously shown that a functional type II GnRH receptor is not present in man. In the present study, we show that GnRH agonists and selective GnRH antagonists exert potent antiproliferative effects on JEG-3 choriocarcinoma, benign prostate hyperplasia (BPH-1), and HEK293 cells stably expressing the type I GnRH receptor. This antiproliferative action occurs through a G{alpha}i-mediated activation of stress-activated protein kinase pathways, resulting in caspase activation and transmembrane transfer of phosphatidlyserine to the outer membrane envelope. Structurally related antagonistic GnRH analogs displayed divergent antiproliferative efficacies but demonstrated equal efficacies in inhibiting GnRH-induced G{alpha}q-based signaling. Therefore the ability of GnRH receptor antagonists to exert an antiproliferative effect on reproductive tumors may be dependent on ligand-selective activation of the G{alpha}i-coupled form of the type I GnRH receptor.




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